ORCID Profile
0000-0001-5886-2656
Current Organisation
Tufts University
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Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2008
DOI: 10.1161/ATVBAHA.108.163931
Abstract: Objective— To investigate mechanisms underlying gender differences in serum lipoprotein concentrations, the kinetic behavior of apoB-100 was assessed. Methods and Results— Twenty subjects ( years 12 men and 8 premenopausal women) were provided a Western diet for 4 to 6 weeks, after which the kinetics of apoB-100 in triglyceride-rich, intermediate-density, and low-density lipoprotein (TRL, IDL, and LDL) were determined in the fed state. Nonfasting plasma TC, LDL-C, and triglyceride concentrations were 23%, 34%, and 57% lower, respectively, in the women compared with men. Plasma TRL and LDL apoB 100 pool sizes were lower by 40% and 30%, respectively. These differences were accounted for by higher TRL and LDL apoB 100 fractional catabolic rates (FCR), rather than differences in production rates (PR). Plasma TRL-C and LDL-C were positively correlated with TRL and LDL apoB 100 concentrations and pool size, and negatively correlated with TRL and LDL apoB 100 FCR (women: r =−0.59, P .01 and r =−0.54, P .04, and men: r =−0.43, P .05 and r =−0.44, P .05). No significant associations were observed between plasma TRL-C and LDL-C and PR. Conclusions— These data suggest the mechanism for lower TRL-C and LDL-C concentrations in women was determined predominantly by higher TRL and LDL FCR rather than lower PR. This could explain, in part, the lower CVD risk in premenopausal women relative to men.
Publisher: Elsevier BV
Date: 02-2013
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2008
DOI: 10.1161/ATVBAHA.108.164541
Abstract: Objectives— Extended-release niacin effectively lowers plasma TG levels and raises plasma high-density lipoprotein (HDL) cholesterol levels, but the mechanisms responsible for these effects are unclear. Methods and Results— We examined the effects of extended-release niacin (2 g/d) and extended-release niacin (2 g/d) plus lovastatin (40 mg/d), relative to placebo, on the kinetics of apolipoprotein (apo) A-I and apoA-II in HDL, apoB-100 in TG-rich lipoproteins (TRL), intermediate-density lipoproteins (IDL) and low-density lipoproteins (LDL), and apoB-48 in TRL in 5 men with combined hyperlipidemia. Niacin significantly increased HDL cholesterol and apoA-I concentrations, associated with a significant increase in apoA-I production rate (PR) and no change in fractional catabolic rate (FCR). Plasma TRL apoB-100 levels were significantly lowered by niacin, accompanied by a trend toward an increase in FCR and no change in PR. Niacin treatment significantly increased TRL apoB-48 FCR but had no effect on apoB-48 PR. No effects of niacin on concentrations or kinetic parameters of IDL and LDL apoB-100 and HDL apoA-II were noted. The addition of lovastatin to niacin promoted a lowering in LDL apoB-100 attributable to increased LDL apoB-100 FCR. Conclusion— Niacin treatment was associated with significant increases in HDL apoA-I concentrations and production, as well as enhanced clearance of TRL apoB-100 and apoB-48.
Publisher: Elsevier BV
Date: 06-2012
DOI: 10.1194/JLR.M019570
Publisher: American Physiological Society
Date: 04-2016
DOI: 10.1152/AJPREGU.00198.2015
Abstract: The loss of skeletal muscle mass is observed in many pathophysiological conditions, including aging and obesity. The loss of muscle mass and function with aging is defined as sarcopenia and is characterized by a mismatch between skeletal muscle protein synthesis and breakdown. Characteristic metabolic features of both aging and obesity are increases in intramyocellular lipid (IMCL) content in muscle. IMCL accumulation may play a mechanistic role in the development of anabolic resistance and the progression of muscle atrophy in aging and obesity. In the present study, aged and high-fat fed mice were used to determine mechanisms leading to muscle loss. We hypothesized the accumulation of bioactive lipids in skeletal muscle, such as ceramide or diacylglycerols, leads to insulin resistance with aging and obesity and the inability to activate protein synthesis, contributing to skeletal muscle loss. We report a positive association between bioactive lipid accumulation and the loss of lean mass and muscle strength. Obese and aged animals had significantly higher storage of ceramide and diacylglycerol compared with young. Furthermore, there was an attenuated insulin response in components of the mTOR anabolic signaling pathway. We also observed differential increases in the expression of inflammatory cytokines and the phosphorylation of IκBα with aging and obesity. These data challenge the accepted role of increased inflammation in obesity-induced insulin resistance in skeletal muscle. Furthermore, we have now established IκBα with a novel function in aging-associated muscle loss that may be independent of its previously understood role as an NF-κB inhibitor.
Publisher: Elsevier BV
Date: 03-2005
DOI: 10.1016/J.METABOL.2004.10.001
Abstract: The metabolism of apolipoproteins (apo) (a) and B-100 within plasma lipoprotein (a) [Lp(a)] was examined in the fed state in 23 subjects aged 41 to 79 years who received a primed-constant infusion of [5,5,5-2H3] leucine over 15 hours. Lipoprotein (a) was isolated from the whole plasma using a lectin affinity-based method. Apolipoprotein (a) and apoB-100 were separated by gel electrophoresis, and tracer enrichment of each apolipoprotein was measured using gas chromatography/mass spectrometry. Data were fit to a multicompartmental model to determine fractional catabolic rates (FCRs) and secretion rates (SRs). The FCRs of apo(a) and apoB-100 (mean +/- SEM) within plasma Lp(a) were significantly different (0.220 +/- 0.030 pool/d and 0.416 +/- 0.040 pool/d, respectively P < .001). Apolipoprotein (a) SR (0.50 +/- 0.08 mg/[kg per d]) was significantly lower than that of apoB-100 SR (1.53 +/- 0.22 mg/[kg per d] P < .001) of Lp(a). Plasma concentrations of Lp(a) were correlated significantly with both apo(a) SR and apoB-100 SR (r = 0.837 and r = 0.789, respectively P < .001) and negatively with apo(a) FCR and Lp(a) apoB-100 FCR (r = -0.547 and r = -0.717, respectively P < .01). These data implicate different metabolic fates for apo(a) and apoB-100 within Lp(a) in the fed state. We therefore hypothesize that apo(a) does not remain covalently linked to a single apoB-100 lipoprotein but that it rather reassociates at least once with another apoB-100 particle, probably newly synthesized, during its plasma metabolism.
Publisher: Elsevier BV
Date: 03-2008
Publisher: Elsevier BV
Date: 04-2016
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2004
DOI: 10.1161/01.ATV.0000137975.14996.DF
Abstract: Objective— Our purpose was to determine the relationship between apolipoprotein (apo) A-I and apoB-48 and apoB-100 metabolism in moderately hypercholesterolemic humans. Methods and Results— The kinetics of apoA-I within high-density lipoprotein (HDL), apoB-48 and apoB-100 within triglyceride-rich lipoproteins, and apoB-100 within intermediate-density lipoprotein and low density-lipoprotein (LDL) were examined with a primed constant infusion of [5,5,5- 2 H 3 ] leucine in the fed state (hourly feeding) in 23 subjects after consumption of a 36% total fat diet. Lipoproteins were isolated by ultracentrifugation apolipoproteins by SDS-PAGE gels and isotope enrichment assessed by gas chromatograph/mass spectrometry. Kinetic parameters were calculated by multicompartmental modeling of the data with SAAM II. ApoA-I production rate (PR) was correlated with LDL apoB-100 pool size (PS r =0.49 P =0.017) and LDL cholesterol ( r =0.61 P =0.002), whereas apoA-I fractional catabolic rate (FCR) was inversely correlated with apoB-48 FCR ( r =−0.40 P =0.05) but not with very low-density lipoprotein apoB-100 FCR. Conclusions— Two links exist between apoA-I and apoB kinetics: 1) when LDL apoB-100 PS is high, there is increased apoA-I PR and 2) delayed chylomicron remnant clearance (represented by apoB-48 FCR) is associated with enhanced apoA-I FCR, a finding indicating that alterations in intestinal lipoproteins may be more important in determining HDL cholesterol levels than changes in liver lipoproteins.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2004
DOI: 10.1161/01.ATV.0000128410.23161.BE
Abstract: Objective— To determine mechanisms contributing to decreased high-density lipoprotein cholesterol (HDL-C) and increased low-density lipoprotein cholesterol (LDL-C) concentrations associated with hydrogenated fat intake, kinetic studies of apoA-I, apoB-100, and apoB-48 were conducted using stable isotopes. Methods and Results— Eight postmenopausal hypercholesterolemic women were provided in random order with 3 diets for 5-week periods. Two-thirds of the fat was soybean oil (unsaturated fat), stick margarine (hydrogenated fat), or butter (saturated fat). Total and LDL-C levels were highest after the saturated diet ( P .05 saturated versus unsaturated) whereas HDL-C levels were lowest after the hydrogenated diet ( P .05 hydrogenated versus saturated). Plasma apoA-I levels and pool size (PS) were lower, whereas apoA-I fractional catabolic rate (FCR) was higher after the hydrogenated relative to the saturated diet ( P .05). LDL apoB-100 levels and PS were significantly higher, whereas LDL apoB-100 FCR was lower with the saturated and hydrogenated relative to the unsaturated diet. There was no significant difference among diets in apoA-I or B-100 production rates or apoB-48 kinetic parameters. HDL-C concentrations were negatively associated with apoA-I FCR ( r =−0.56, P =0.03) and LDL-C concentrations were negatively correlated with LDL apoB-100 FCR ( r =−0.48, P =0.05). Conclusions— The mechanism for the adverse lipoprotein profile observed with hydrogenated fat intake is determined in part by increased apoA-I and decreased LDL apoB-100 catabolism.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2005
DOI: 10.1161/01.ATV.0000172629.12846.B8
Abstract: Objective— To determine mechanisms contributing to the altered lipoprotein profile associated with aging and menopause, apolipoprotein B-100 (apoB-100) and apoA-I kinetic behavior was assessed. Methods and Results— Eight premenopausal (25±3 years) and 16 postmenopausal (65±6 years) women consumed for 6 weeks a standardized Western diet, at the end of which a primed-constant infusion of deuterated leucine was administered in the fed state to determine the kinetic behavior of triglyceride-rich lipoprotein (TRL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL) apoB-100, and high-density lipoprotein (HDL) apoA-I. Data were fit to a multicompartmental model using SAAM II to calculate fractional catabolic rate (FCR) and production rate (PR). Total cholesterol, LDL cholesterol (LDL-C), TRL-C, and triglyceride levels were higher (50%, 55%, 130%, and 232%, respectively) in the postmenopausal compared with the premenopausal women, whereas HDL-C levels were similar. Plasma TRL, IDL, and LDL-apoB-100 levels and pool sizes (PS) were significantly higher in the postmenopausal than premenopausal women. These differences were accounted for by lower TRL, IDL, and LDL apoB-100 FCR ( P .05), with no difference in PR. There was no significant difference between groups in HDL-C levels or apoA-I kinetic parameters. Plasma TRL-C concentrations were negatively correlated with TRL apoB-100 FCR ( r =−0.46 P .05) and positively correlated with PR ( r =0.62 P .01). Plasma LDL-C concentrations were negatively correlated with LDL apoB-100 FCR ( r =−0.70 P .001) but not PR. Conclusions— The mechanism for the increase in TRL and LDL apoB-100 PS observed in the postmenopausal women was determined predominantly by decreased TRL and LDL catabolism rather than increased production. No differences were observed in HDL apoA-I kinetics between groups.
Publisher: Wiley
Date: 26-03-2015
DOI: 10.1007/S11745-015-4005-0
Abstract: Dose-associated effects of rosuvastatin on the metabolism of apolipoprotein (apo) B-100 in triacylglycerol rich lipoprotein (TRL, d < 1.019 g/ml) and low density lipoprotein (LDL) and of apoA-I in high density lipoprotein (HDL) were assessed in subjects with combined hyperlipidemia. Our primary hypothesis was that maximal dose rosuvastatin would decrease the apoB-100 production rate (PR), as well as increase apoB-100 fractional catabolic rate (FCR). Eight subjects received placebo, rosuvastatin 5 mg/day, and rosuvastatin 40 mg/day for 8 weeks each in sequential order. The kinetics of apoB-100 in TRL and LDL and apoA-I in HDL were determined at the end of each phase using stable isotope methodology, gas chromatography-mass spectrometry, and multicompartmental modeling. Rosuvastatin at 5 and 40 mg/day decreased LDL cholesterol by 44 and 54% (both P < 0.0001), triacylglycerol by 14% (ns) and 35% (P < 0.01), apoB by 30 and 36% (both P < 0.0001), respectively, and had no significant effects on HDL cholesterol or apoA-I levels. Significant decreases in plasma markers of cholesterol synthesis and increases in cholesterol absorption markers were observed. Rosuvastatin 5 and 40 mg/day increased TRL apoB-100 FCR by 36 and 46% (both ns) and LDL apoB-100 by 63 and 102% (both P < 0.05), respectively. HDL apoA-I PR increased with low dose rosuvastatin (12%, P < 0.05) but not with maximal dose rosuvastatin. Neither rosuvastatin dose altered apoB-100 PR or HDL apoA-I FCR. Our data indicate that maximal dose rosuvastatin treatment in subjects with combined hyperlipidemia resulted in significant increases in the catabolism of LDL apoB-100, with no significant effects on apoB-100 production or HDL apoA-I kinetics.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2006
DOI: 10.1161/01.ATV.0000199248.53590.E1
Abstract: Objective— Plasma high-density lipoprotein (HDL) cholesterol levels are inversely correlated with the risk of developing coronary heart disease. Hormonal replacement therapy (HRT) affects plasma HDL cholesterol levels, with estrogen increasing HDL cholesterol levels and progestins blunting this effect. This study was designed to assess the mechanism responsible for these effects. Materials and Methods— HDL apolipoprotein A-I (apoA-I) kinetics were studied in 8 healthy postmenopausal women participating in a double-blind, randomized, crossover study comprising 3 phases: placebo, conjugated equine estrogen (CEE) (0.625 mg/d), and CEE plus medroxyprogesterone acetate (MPA) (2.5 mg/d). Compared with placebo, treatment with CEE resulted in an increase in apoA-I pool size (+20%, P .01) because of a significant increase in apoA-I production rate (+47%, P .05) and no significant changes in apoA-I fractional catabolic rate. Compared with the CEE alone phase, treatment with the CEE plus MPA resulted in an 8% ( P .02) reduction in apoA-I pool size and a significant reduction in apoA-I production rate (−13%, P .04), without changes in apoA-I fractional catabolic rate. Conclusion— Postmenopausal estrogen replacement increases apoA-I levels and production rate. When progestin is added to estrogen, it opposes these effects by reducing the production of apoA-I.
Publisher: Elsevier BV
Date: 08-2007
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2006
DOI: 10.1161/01.ATV.0000219695.84644.56
Abstract: Objective— Cholesteryl ester transfer protein (CETP) inhibition with torcetrapib not only increases high-density lipoprotein cholesterol levels but also significantly reduces plasma triglyceride, low-density lipoprotein (LDL) cholesterol, and apolipoprotein B (apoB) levels. The goal of the present study was to define the kinetic mechanism(s) by which CETP inhibition reduces levels of apoB-containing lipoproteins. Methods and Results— Nineteen subjects, 9 of whom were pretreated with 20 mg atorvastatin, received placebo for 4 weeks, followed by 120 mg torcetrapib once daily for 4 weeks. Six subjects in the nonatorvastatin group received 120 mg torcetrapib twice daily for an additional 4 weeks. After each phase, subjects underwent a primed-constant infusion of deuterated leucine to endogenously label newly synthesized apoB to determine very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL) and LDL apoB100 production, and fractional catabolic rates (FCRs). Once-daily 120 mg torcetrapib significantly reduced VLDL, IDL, and LDL apoB100 pool sizes by enhancing the FCR of apoB100 within each fraction. On a background of atorvastatin, 120 mg torcetrapib significantly reduced VLDL, IDL, and LDL apoB100 pool sizes. The reduction in VLDL apoB100 was associated with an enhanced apoB100 FCR, whereas the decreases in IDL and LDL apoB100 were associated with reduced apoB100 production. Conclusions— These data indicate that when used alone, torcetrapib reduces VLDL, IDL, and LDL apoB100 levels primarily by increasing the rate of apoB100 clearance. In contrast, when added to atorvastatin treatment, torcetrapib reduces apoB100 levels mainly by enhancing VLDL apoB100 clearance and reducing production of IDL and LDL apoB100.
Publisher: Elsevier BV
Date: 03-2013
Publisher: American Physiological Society
Date: 12-2012
DOI: 10.1152/JAPPLPHYSIOL.00412.2012
Abstract: One of the most fundamental adaptive physiological events is the response of skeletal muscle to high-intensity resistance exercise, resulting in increased protein synthesis and ultimately larger muscle mass. However, muscle growth in response to contraction is attenuated in older humans. Impaired contractile-induced muscle growth may contribute to sarcopenia: the age-associated loss of muscle mass and function that is manifested by loss of strength, contractile capacity, and endurance. We hypothesized that the storage of ceramide would be increased in older in iduals and this would be associated with increases in NFκB signaling and a decreased anabolic response to exercise. To test this hypothesis we measured ceramides at rest and anabolic and NFκB signaling after an acute bout of high-intensity resistance exercise in young and older males. Using lipidomics analysis we show there was a 156% increase in the accumulation of C16:0-ceramide ( P 0.05) and a 30% increase in C20:0-ceramide ( P 0.05) in skeletal muscle with aging, although there was no observable difference in total ceramide. C16:0-ceramide content was negatively correlated ( P = 0.008) with lower leg lean mass. Aging was associated with a ∼60% increase in the phosphorylation of the proinflammatory transcription factor NFκB in the total and nuclear cell fractions ( P 0.05). Furthermore, there was an attenuated activation of anabolic signaling molecules such as Akt ( P 0.05), FOXO1 ( P 0.05), and S6K1 ( P 0.05) after an acute bout of high-intensity resistance exercise in older males. We conclude that ceramide may have a significant role in the attenuation of contractile-induced skeletal muscle adaptations and atrophy that is observed with aging.
No related grants have been discovered for Gregory Dolnikowski.